The present invention is directed to the C-45T polymorphism in the Sp1 binding region of the cholecystokinin (CCK) gene and the role of genetic variants in the CCK gene as a risk factor for smoking and unsuccessful smoking cessation in women.
The publications and other materials used herein to illuminate the background of the invention or provide additional details respecting the practice, are incorporated by reference, and for convenience are respectively grouped in the appended Lists of References.
Despite knowledge of the potential consequences, after a decade of a decrease in the percent of the U.S. population that smokes, the decline has leveled off at about 25 percent. See Centers for Disease Control and Prevention, (1995 Report); Giovino et al. (1995); and Kendrick and Merritt, 1996. Approximately half of smokers are women, and women find it particularly difficult to stop smoking because of fears of gaining weight. See Crisp et al., 1999; Klesges et al., 1999; and Sorensin and Pechacek, 1987. The identification of the mechanism by which nicotine influences appetite could lead to the identification of more effective smoking cessation programs, especially in women. In this regard CCK regulates weight by producing a feeling of satiety (Smith and Gibbs, 1994), and animal studies show that both accurate and chronic exposure to nicotine results in increased plasma CCK levels and weight loss (Chowdhury et al., 1989; Chowdhury et al., 1991; and Winders and Grunberg, 1989). The weight loss is associated with a decrease in food intake and an increase in metabolism, as well as decreases in plasma glucose and insulin levels (Chowdhury et al., 1990; Crawley and Corwin, 1994). Cholecystokinin (CCK), one of the most abundant neuropeptides in the brain, plays a role in a wide range of behaviors in addition to feeding including learning, memory, anxiety, pain, drug dependence and withdrawal. See Costall et al., 1991; Crawley and Corwin, 1994; Fink et al., 1999. Rasmussen et al. (1996) reported that a CCK antagonist significantly decreased the symptoms of nicotine withdrawal in animals.
The identification of a C-45T polymorphism in the Sp1 binding cis-element of the CCK gene (Harada et al. 1998) has allowed the investigation of the role of CCK variants in various human behaviors. Harada et al. (Harada et al. 1998) reported a significant increase in the frequency of the T allele in Japanese alcoholics compared to controls, but this was not replicated in Japanese in a study by Ishiguro et al. (Ishiguro et al. 1999). Studies of a C-36T mutation, also in the Sp1 binding region, have suggested a role of the CCK gene in panic disorder in some (Wang, et al. 1998) but not all (Kennedy et al. 1999) studies. Based on the above observations we hypothesized that the T allele of the C-45T polymorphism of the CCK gene might be associated with BMI (Body Mass Index) and/or smoking in women, and might provide insights into the role of smoking in weight control. Other polymorphisms of the CCK gene, e.g., the C-36T polymorphism, might also be associated with BMI and/or smoking in women, and might provide further insights into the role of smoking in weight control. Because the T allele of the C-45T polymorphism of the CCK gene may be associated with smoking in women, genetically defective CCK genes could play an important role as a risk factor determinant for nicotine dependence and unsuccessful cessation thereof.
Thus, there is a continued need to investigate genes involved in the neuropathways of the brain to identify risk factors for smoking and markers for a genetic predisposition to problems with smoking cessation which can be used for diagnosis of the above-described disorders and for guiding drug therapy, e.g., for the identification of agents which may be useful aids for smoking cessation.
The present invention is directed to the C-45T polymorphism in the Sp1 binding region of the CCK gene and the role of genetic variants in the CCK gene as a risk factor for smoking and unsuccessful smoking cessation in women. In particular, the present invention is directed to the discovery that 12.3% of women who never smoked carried the T allele. Carriers of the T allele increased to 26.8% for women who had smoked but had stopped, and to 75% for women who were unable to quit smoking (pxe2x89xa60.00009). Using the discovery of the present invention, CCK acting agents are useful aids for smoking cessation. Now that the C-45T polymorphism of the CCK gene has been discovered, gene libraries can be searched for other polymorphisms that are in linkage disequilibrium with the one shown.
In a one aspect, the present invention is directed to the role of genetic variants in the CCK gene as a risk factor for smoking and unsuccessful smoking cessation in women.
In a second aspect of the invention, analysis of the T allele of the C-45T polymorphism of the CCK gene is provided for diagnosis of subjects to identify women who will be candidates for CCK acting smoking cessation agents. The diagnostic method comprises analyzing the DNA sequence of the CCK gene for the presence of the C-45T polymorphism of an individual to be tested and comparing it with the DNA sequence of the native, non-variant genes. In a second embodiment, the CCK gene of an individual to be tested is screened for polymorphisms associated with smoking in women. The ability to predict an inability of a subject to quit smoking will enable physicians to treat such disorders with appropriate medical therapies.
In a third aspect of the present invention, the polymorphisms in the CCK gene are used for drug screening and testing.
In a fourth aspect of the present invention, the CCK gene is analyzed for other polymorphisms associated with smoking.
In a fourth aspect of the present invention, gene libraries are searched for other polymorphisms that are in linkage disequilibrium with the C-45T polymorphism.